Ru catalyzed acyloxylation process for preparing 4-acyloxyazetidinone derivatives

ABSTRACT

A process for preparing a 4-acyloxyazetidinone or a derivative thereof represented by formula (IV): ##STR1## wherein R 1  represents a hydrogen atom, a lower alkyl group, a hydroxyethyl group, or a protected hydroxyethyl group; R 3  represents an alkyl group having from 1 to 10 carbon atoms which may be substituted with a halogen atom, a cyano group, a lower alkoxy group or a phenyl group, or a substituted or unsubstituted phenyl group, provided that the α-positioned carbon atom of said alkyl group should not have more than two halogen atoms; and R 4  represents a hydrogen atom, a lower alkyl group, or a lower alkoxycarbonyl group, 
     which is useful as an intermediate for penera antibiotics is disclosed, comprising reacting azetidinone or a derivative thereof represented by formula (II): ##STR2## wherein R 1  is as defined above, and R 2  represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, or a carboxyl group, 
     with a carboxylic acid represented by formula (III): 
     
         R.sup.3 COOH                                               (III) 
    
     wherein R 3  is as defined above, 
     in the presence of (1) a transition metal compound selected from a ruthenium compound, an osmium compound, and a cobalt compound, (2) an aldehyde having 2 or more carbon atoms, provided that the carbon atom at the α-position thereof should not have two or more halogen atoms, and (3) oxygen. The compound (IV) can be prepared with safety through simple and easy operations.

This is a divisional of application Ser. No. 07/869, 171, filed Apr. 16,1992 U.S. Pat. No. 5, 288, 862.

FIELD OF THE INVENTION

This invention relates to a process for preparing a useful intermediatefor synthesizing penem antibiotics exemplified by thienamycin. Moreparticularly, it relates to a process for preparing a4-acyloxyazetidinone represented by formula (IV): ##STR3## wherein R¹represents a hydrogen atom, a lower alkyl group, a hydroxyethyl group,or a protected hydroxyethyl group; R³ represents an alkyl group havingfrom 1 to 10 carbon atoms which may be substituted with a halogen atom,a cyano group, a lower alkoxy group or a phenyl group, or a substitutedor unsubstituted phenyl group, provided that the α-positioned carbonatom of said alkyl group should not have more than two halogen atoms;and R⁴ represents a hydrogen atom, a lower alkyl group, or a loweralkoxycarbonyl group.

BACKGROUND OF THE INVENTION

Penem antibiotics represented by thienamycin have attracted attention asmedicines because of their broad antimicrobial spectra.

Various processes for preparing penera antibiotics have been reported,e.g., in Kametani, Heterocycles, Vol. 17, pp. 463-506 (1982) andShibuya, et al., Yuki Gosei Kaqaku, Vol. 41, p. 62 (1983). Among theknown processes, a process using a 4-acyloxyazetidinone or a derivativethereof represented by formula (IV) as an intermediate is particularlyadvantageous in that the compound of formula (IV) is reactive withvarious nucleophilic agents, leading to various penem antibiotics.

Known processes for preparing the intermediate compound of formula (IV)include oxidation of 4-carboxyazetidinone derivatives with leadtetraacetate (Tetrahedron Letters, Vol. 23, p. 2293 ( 1982 ) ),electrode oxidation of 4-carboxyazetidinone derivatives (TetrahydronLetters, Vol. 29, p. 1409 (1988)), oxidation of 4-acetylazetidinonederivatives with m-chloroperbenzoic acid (JP-A-61-50964) (the term"JP-A" as used herein means an "unexamined published Japanese patentapplication"), and treatment of 4-silyloxyazetidinone derivatives withacetic anhydride (European Patent 247, 378).

In order to introduce an acetoxy group to the 4-position of theazetidinone skeleton according to any of the above-described processes,it is necessary to synthesize an azetidinone compound having a specificsubstituent group at the 4 -position, via which an acetoxy group is tobe introduced. However, preparation of an azetidinone compound havingsuch a specific substituent group at the 4-position involves complicatedsteps and, also, it has been difficult to convert the substituent groupat the 4-position to an acetoxy group. Hence, these conventionalprocesses are not regarded advantageous as industrial techniques.

Other processes for synthesizing 4-acyloxyazetidinone derivatives aredescribed in JP-A-3-48681 and JP-A-3-56481, but they have industrialdisadvantages such as low yields, in addition to the above-describedproblems.

On the other hand, it has lately been suggested to react an azetidinonecompound with acetic acid and a peroxide as an oxidizing agent in thepresence of a ruthenium compound catalyst to introduce an acetoxy groupas disclosed in JP-A-2-231471. However, many of peroxides useful as anoxidizing agent are generally dangerous, demanding meticulous care notonly in storage and transportation but on actual use. Besides the safetyproblem, they are expensive.

Further, 4-acetoxyazetidinone derivatives are still unsatisfactory dueto the insufficient activity of the 4-positioned acetoxy group as areleasable group, and it is desired to develop an intermediate having amore active releasable group. It is known that the activity of areleasable group increases and becomes more advantageous in thedisplacement reaction at the 4-position according as its acidityincreases (see W. N. Speckamp and H. Hiemstra, Tetrahedron, Vol. 41, p.4367 (1985)). From this point of view, it is anticipated that achloroacetoxy group, a cyanoacetoxy group, a bromoacetoxy group, adichloroacetoxy group, a dibromoacetoxy group, and the like are moreactive than an acetoxy group.

In particular, while carbon nucleophilic agents used in reactions forforming a carbon-to-carbon bond by using a Lewis acid, etc., such asketene silyl acetal and silyl enol ether, are relatively labile underthe reaction conditions, such lability would be compensated for byincreasing the reaction rate by using an intermediate with theabove-mentioned active releasable group. Nevertheless, it has beendifficult to synthesize such an intermediate from 4-acetoxy compoundsthrough conventional techniques such as ester exchange reaction.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a process for preparinga 4-acyloxyazetidinone compound by introducing an acyloxy group to the4-position of an azetidinone compound with safety and in good yieldthrough simple and easy operations.

In the light of the above situation, the inventors have conductedextensive investigations. As a result, it has now been found that theabove object of the present invention is accomplished by reacting anazetidinone compound and a carboxylic acid in the presence of (1) atransition metal compound selected from a ruthenium compound, an osmiumcompound, and a cobalt compound, (2) an aldehyde, and (3) oxygen. Thepresent invention has been completed based on this finding.

The present invention provides a process for preparing a4-acyloxyazetidinone or a derivative thereof represented by formula(IV), which comprises reacting azetidinone or a derivative thereofrepresented by formula (II): ##STR4## wherein R¹ is as defined above,and R² represents a hydrogen atom, a lower alkyl group, a loweralkoxycarbonyl group, or a carboxyl group,

with a carboxylic acid represented by formula (III):

    R.sup.3 COOH                                               (III)

wherein R³ is as defined above,

in the presence of (1) a transition metal compound selected from aruthenium compound, an osmium compound, and a cobalt compound, (2) analdehyde having 2 or more carbon atoms in which the carbon atom at theα-position should not have two or more halogen atoms, and (3) oxygen.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, the term "lower" in the "lower alkyl group" or"lower alkoxy group" usually means 1 to 5 carbon atoms, and the term"lower" in the "lower alkanoyloxy group" usually means 2 to 6 carbonatoms.

Examples of the starting azetidinone compound of formula (II) which canbe used in the present invention are azetidin-2-one,3-methylazetidin-2-one, 3-ethylazetidin-2-one, 3-(protected)hydroxyethylazetidin-2-one, 3-methyl-4-carboxyazetidinone,3-ethyl-4-carboxyazetidin-2-one, 3-(protected )hydroxyethyl-4-carboxyazetidin-2-one, 4-methylazetidin-2-one,4-carboxyazetidin-2-one, and 4-methoxycarbonylazetidin-2-one. Theprotective groups for a hydroxyl group include those commonly employedfor hydroxyl group protection in lactam compounds, e.g., silyl groups(e.g., trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,diphenyl-t-butylsilyl ), a benzyloxycarbonyl group, ap-nitrobenzyloxycarbonyl group, and an o-nitrobenzyloxycarbonyl group.

Of the compounds of formula (II), those wherein R¹ is a protected orunprotected hydroxyethyl group, and R³ is a hydrogen atom can beprepared, for example, in accordance with the processes described inBer., Vol. 92, p. 1599 (1959) and JP-A-2-231471.

Of the carboxylic acids of formula (III), those wherein is an alkylgroup having from 1 to 10 carbon atoms include acetic acid, propionicacid, butyric acid, hexanoic acid, heptanoic acid, octanoic acid,decanoic acid, and isobutyric acid. The number of substituent groups onthe alkyl group R³ is not particularly limited except that the number ofhalogen atoms on the α-positioned carbon atom, if any, is limited to 1or 2. If a carboxylic acid having three halogen atoms at the α-positionthereof, e.g., trichloroacetic acid, is used, some influence is exertedonto the substrate, failing to obtain a desired compound.

Examples of carboxylic acids (III) wherein R³ is a halogen-substitutedalkyl group include chloroacetic acid, dichloroacetic acid, bromoaceticacid, dibromoacetic acid, 3-chloropropionic acid, 2-bromohexanoic acid,and 2-bromooctanoic acid. Examples of carboxylic acids (III) wherein R³is a lower alkoxy-substituted alkyl group include methoxyacetic acid and3-ethoxypropionic acid. Examples of carboxylic acids (III) wherein R³ isa cyano-substituted alkyl group include cyano-acetic acid. Examples ofcarboxylic acids (III) wherein R³ is a phenyl-substituted alkyl groupinclude phenylacetic acid, 2-phenylbutyric acid, and 6-phenylhexanoicacid. Examples of carboxylic acids (III) wherein R³ is a substituted orunsubstituted phenyl group include benzoic acid, p-chlorobenzoic acid,p-ethoxybenzoic acid, and 2, 4-dinitrobenzoic acid.

The transition metal compound used in the present invention serves as acatalyst.

Ruthenium compounds include the following compounds (a) to (j).

(a) Compounds represented by formula (V):

    RuA.sub.3                                                  (V)

wherein A represents a halogen atom, a lower alkanoyloxy group, oracetylacetonato.

Specific examples of the compounds (V) are ruthenium trichloride,ruthenium tribromide, ruthenium triiodide, and hydrates of theseruthenium halides; ruthenium acetylacetonate; and ruthenium acetate.

(b) Metallic ruthenium or ruthenium-on-carrier:

Metallic ruthenium includes ruthenium powder. Examples of theruthenium-on-carrier include ruthenium-on-carbon, ruthenium-on-graphite,ruthenium-on-alumina, ruthenium-on-silica, ruthenium-on-silica-alumina,ruthenium-on-zeolite, ruthenium-on-iron oxide, ruthenium-on-zirconiumoxide, and ruthenium-on-diatomaceous earth.

(c) Compounds represented by formula (VI):

    [Ru.sub.r Cl.sub.m H.sub.n (N.sub.2).sub.j B.sub.p ].sub.q (VI)

wherein B represents PR⁵ ₃, wherein R⁵ represents a phenyl group whichmay be substituted with a lower alkyl group or a lower alkoxy group, ora lower alkyl group; when R⁵ is a phenyl group which may be substitutedwith a lower alkyl group or a lower alkoxy group, (i) m=0, n=2, j-0,p=4, q=1, and r=1, (ii) m=0, n=2, j=1, p=3, q=1, and r=1, (iii) m=1,n=1, j=0, p=3, q=1, and r=1, or (iv) m=2, n=0, j=0, p=3, q=1, and r=1;and when R⁵ is a lower alkyl group, (i') m=3, n=0, j=0, p=2, q=2, andr=1 or (ii' ) m=5, n=0, j=0, p=3, q=1, and r=2.

Specific examples of the compounds (VI) are RuHCl(PPh₃)₃, RuCl₂ (PPh₃)₃,RuH₂ (PPh₃)₃, RuH₂ (N₂)(PPh₃)₃, [RuCl₃ (PBu₃)₂ ]₂, and Ru₂ Cl₅ (PBu₃)₃,wherein Ph represents a phenyl group, and Bu represents a butyl group.

(d) Compounds represented by formula (VII):

    [RuY.sub.2 L].sub.m                                        (VII)

wherein Y represents a chlorine atom, a bromine atom, or an iodine atom;m represents a positive integer; and L represents 1, 5-cyclooctadiene,norbornadiene, cyclooctatetraene, cycloheptatriene, benzene, or loweralkyl-substituted benzene.

Specific examples of the compounds (VII) are RuCl₂ (COD), RuCl₂ (NBD),RuCl₂ (COT), RuBr₂ (COD), RuBr₂ (NBD), RuBr₂ (COT), RuI₂ (COD), RuI₂(NBD), RuI₂ (COT), RuCl₂ (CHPT), RuBr₂ (CHPT), RuCl₂ (C₆ H₆), RuBr₂ (C₆H₆), RuI₂ (C₆ H₆), RuCl₂ (C₆ H₅ CH₃), RuCl₂ [p-C₆ H₄ (CH₃)₂ ], RuCl₂ [1,3, 5-C₆ H₃ (CH₃)₃ ], and RuCl[p-cymene], wherein COD represents 1,5-cyclooctadiene; NBD represents norbornadiene; COT representscyclooctatetraene; and CHPT represents cycloheptatriene.

(e) Compounds represented by formula (VIII):

    Ru.sub.x H.sub.y Cl.sub.z (R-BINAP).sub.2 (S).sub.p        (VIII)

wherein R-BINAP represents tertiary phosphine represented by formula(IX): ##STR5## wherein R represents a hydrogen atom, a methyl group, ora t-butyl group; (S) represents a tertiary amine; y represents 0 or 1;when y is 0, x=2, z=4, and p=1; and when y is 1, x=1, z=1, and p=0,

(f) Compounds represented by formula (X): ##STR6## wherein X representsa hydrogen atom, an amino group, an acetylamino group, or a sulfonegroup; R⁶ represents a hydrogen atom or a lower alkyl group; R⁷ and R⁸each represent a lower alkyl group, a halogenated lower alkyl group, aphenyl group, a lower alkyl-substituted phenyl group, an α-aminoalkylgroup, or an α-aminophenylalkyl group, or they are taken together toform an alkylene group; and n represents 1 or 2,

(g) Compounds represented by formula (XI):

    [RuH.sub.l (R-BINAP).sub.m ]Zn                             (XI)

wherein R-BINAP is as defined above; Z represents ClO₄, BF₄, or PF₆ ; lrepresents 0 or 1; when l is 0, m=1 and n=2; and when l is 1, m=2 andn=1,

(h) Compounds represented by formula (XII):

    [RuT.sub.l M.sub.m (R-BINAP)]K.sub.n                       (XII)

wherein R-BINAP is as defined above; T represents a halogen atom; Mrepresents substituted or unsubstituted benzene or acetonitrile; Krepresents a halogen atom, ClO₄, PF₆, BPh₄ (wherein Ph represents aphenyl group), or BF₄ ; when M is substituted or unsubstituted benzene,l=1, m=1, and n=1; and when M is acetonitrile, when l is 1, m=2 and n=1,and when l is 0, m=4 and n=2,

(i) Ru₃ (CO)₁₂, RuI₂ (CO)₂, Ru₂ Cl₄ (CO)₆, Ru(CO)₅, and Ru(TPP)(CO)-THF,wherein TPP represents tetraphenylporphine; and THF representstetrahydrofuran.

(j) Ru(NO)Cl₃ ·H₂ O, Ru(NO)Br₃ ·H₂ O, K(RuO₄), and Ba(RuO₃ (OH)₂).

The osmium compounds include compounds represented by formula (XIII):

    OsY.sub.3                                                  (XIII)

wherein Y represents a chlorine atom, a bromine atom, or an iodine atom.

Specific examples of the compounds (XIII) are osmium trichloride, osmiumtribromide, osmium triiodide, and hydrates of these osmium halides.

The cobalt compounds include compounds represented by formula (XIV):

    CoW.sub.2                                                  (XIV)

wherein W represents a chlorine atom, a bromine atom, an iodine atom, oran acetoxy group.

Specific examples of the compounds (XIV) are cobalt chloride, cobaltbromide, cobalt iodide, cobalt acetate, and hydrates thereof.

The compounds (VI) can be obtained by the processes described in TheChemical Society of Japan (ed.), SHIN-JIKKEN KAGAKU KOZA, Vol. 12 (YUKIKINZOKU KAGAKU), p. 163, Maruzen (Mar. 20, 1976) and J. C. S. DaltonTrans, p. 2480 (1980). The compounds (VII) can be synthesized by theprocesses disclosed in Chemistry and Ind., p. 1516 (1959), J. C. S., p.3178 (1959), J. Organometal., Vol. 7, p. 487 (1967), and J. C. S.,Dalton Trans, p. 233 (1974). The compound (VII) as produced comprises,in some cases, solely of the compound wherein m is 1 and, in some othercases, a mixture of the compound wherein m is 1 and polymers thereof(i.e., m is 2 or more). For the sake of convenience, the latter compoundwill hereinafter be expressed as a compound wherein m is 1. Thecompounds (VIII), (X), (XI), and (XII) can be prepared by the processesdisclosed in JP-A-61-63690, JP-A-62-265293, JP-A-63-41487, andJP-A-2-191289, respectively.

The aldehydes having 2 or more carbon atoms which can be used in thepresent invention are not particularly restricted and includealkylaldehydes, alkenylaldehydes, and arylatdehydes, each of which maybe substituted provided the α-positioned carbon atom thereof should nothave more than 2 halogen atoms. Examples of the substituted orunsubstituted alkylaldehydes are acetaldehyde, propionaldehyde,butyraldehyde, hexanal, heptanal, octanal, decanal, dodecanal,isopropionaldehyde, isobutyraldehyde, chloroacetaldehyde,dichloroacetaldehyde, fluoroacetaldehyde, bromoacetaldehyde,α-chloropropionaldehyde, α-bromopropionaldehyde, 1-chlorooctanal,phenylacetaldehyde, p-methoxyphenylacetaldehyde,p-chlorophenylacetaldehyde, m-chlorophenylacetaldehyde,cyclohexanecarbaldehyde, and cyclopentanecarbaldehyde. Examples of thesubstituted or unsubstituted alkenylaldehydes are crotonaldehyde,2-pentenal, and 2-hexenal. Examples of the substituted or unsubstitutedarylaldehydes are benzaldehyde, p-chlorobenzaldehyde,m-chlorobenzaldehyde, p-methoxybenzaldehyde, o-methoxybenzaldehyde, 3,4-dimethoxybenzaldehyde, p-methylbenzaldehyde, piperonal,1-formylnaphthalene, and 2-formylnaphthalene.

For obtaining improved yields, it is preferable to use an aldehydecorresponding to the carboxylic acid used.

Oxygen to be used in the reaction may be oxygen gas or anoxygen-containing gas, e.g., air.

The reaction is preferably carried out in the co-presence of acarboxylic acid salt to increase the yield. Any carboxylic acid salts,e.g., sodium acetate, potassium acetate and lithium acetate, may beused, but a salt of the same carboxylic acid used in the reaction ispreferred.

In carrying out the present invention, the compound (II), aldehyde,carboxylic acid (III), and transition metal compound are dissolved orsuspended in an appropriate solvent, and the solution or suspension isstirred at a temperature of from -10° to 80° C., and preferably from 0°to 40° C., for a period of from 0.5 to 15 hours, and preferably from 1to 5 hours, while introducing oxygen or an oxygen-containing gas intothe reaction system. While the order or mode of addition of the startingcompounds, catalyst, etc. are not particularly limited, it isrecommended to add the aldehyde finally.

Examples of useful solvents include methyl acetate, ethyl acetate, butylacetate, acetone, methyl ethyl ketone, methyl butyl ketone,dichloromethane, acetonitrile, and chloroform. Mixtures of thesesolvents are also useful. The aldehyde is used in an amount usually offrom 1 to 5 mole, and preferably from 1.1 to 3 mole, per mole of thecompound (II). The carboxylic acid (III) is used in an amount usually offrom 1 to 15 mole, and preferably from 2 to 10 mole, per mole of thecompound (II). The transition metal compound is used in an amountusually of from 0.001 to 0.1 mole, and preferably from 0.01 to 0.05mole, per mole of the compound (II).

Methods of isolation and purification of the product from the reactionmixture are not restricted. For example, recrystallization and columnchromatography may be performed.

Of the 4-acyloxyazetidinone or derivatives thereof of formula (IV)obtained by the present invention, a substituted acetoxyazetidinonederivative represented by formula (I): ##STR7## wherein t-Bu representsa t-butyl group; Me represents a methyl group; D represents a chlorineatom, a bromine atom, or a cyano group; a represents 1 or 2; and brepresents 2 when a is 1, or b represents 1 when a is 2, is a novelcompound.

The novel compounds of formula (I) exhibit higher activity at the4-positioned releasable group as compared with 4-acetoxyazetidinonecompounds and are therefore superior as intermediates for synthesizingcarbapenem antibiotics.

The above-described process of the present invention holds industrialadvantages in that a 4-acyloxyazetidinone or a derivative thereof (IV)useful as intermediates for penem antibiotics can be prepared withsafety through simple and easy operations.

The present invention is now illustrated in greater detail withreference to Examples, but it should be understood that the presentinvention is not construed as being limited thereto. All the parts,percents, and ratios are by weight unless otherwise indicated.

EXAMPLE 1 Synthesis of 4-Acetoxyazetidin-2-one

In a Schlenk's tube were charged 710 mg (10 mmole) of azetidin-2-one,205 mg (2.5 mole ) of anhydrous sodium acetate, and 130 mg (0.5 mole, 5mole %) of ruthenium chloride trihydrate. After thoroughly displacingthe atmosphere with oxygen, a balloon filled with oxygen was fitted tothe reactor. To the mixture were added 100 ml of ethyl acetate and 5 mlof acetic acid, followed by heating at 40° C. for 30 minutes withstirring. To the reaction mixture was added 1.1 ml (20 mole) ofacetaldehyde all at once while stirring at 40° C., and the reaction wascontinued for an additional 3 hours. The reaction mixture was pouredinto 400 ml of a 10% sodium sulfite aqueous solution and extracted twicewith 500 ml portions of ethyl acetate. The extract was washed with 200ml of a saturated sodium chloride aqueous solution and dried overanhydrous sodium sulfate. The solvent was removed by distillation underreduced pressure, and the residue was purified by silica gel columnchromatography using a 3:1 (by volume) mixed solvent of n-hexane andethyl acetate to obtain 1.14 g (8.8 mmole, percent yield: 88%) of4-acetoxyazetidin-2-one as an oily substance.

EXAMPLES 2 TO 5

4-Acetoxyazetidinone or a derivative thereof shown in Table 1 below wasprepared in the same manner as in Example 1, except for replacing thesubstrate, azetidin-2-one, with each of the azetidinone compounds ofTable 1. In the formulae in Table 1, t-Bu represents a t-butyl group; Merepresents a methyl group; and Ac represents an acetyl group.

                                      TABLE 1                                     __________________________________________________________________________    Example            Produced 4-Acetoxy-                                                                           Yield                                      No.   Substrate    azetidinone Compound                                                                          (%)                                        __________________________________________________________________________           ##STR8##                                                                                   ##STR9##       91                                         3                                                                                    ##STR10##                                                                                  ##STR11##      72                                         4                                                                                    ##STR12##                                                                                  ##STR13##      87                                         5                                                                                    ##STR14##                                                                                  ##STR15##      72                                         __________________________________________________________________________

EXAMPLES 6 TO 14 Synthesis of (1'R, 3R, 4R)-4-Acetoxy-3[(1'-t-butyldimethvlsilyloxy)ethyl]azetidin-2-one

The titled compound was synthesized in the same manner as in Example 1,except for using 458 mg (2 mmole) of (1'R,3S)-3-[(1'-t-butyldimethylsilyloxy)ethyl]azetidin-2-one as a reactionsubstrate, replacing ruthenium chloride as a catalyst with each of thetransition metal compounds shown in Table 2 below, using 41 mg (0.5mmole) of anhydrous sodium acetate, 1 ml of acetic acid, 20 ml of ethylacetate, 0.22 ml (4 mmole) of acetaldehyde, 40 ml of a 10% sodiumsulfite aqueous solution, and 50 ml of a saturated sodium chlorideaqueous solution, and conducting the extraction with two 100 ml portionsof n-hexane.

The yield in each reaction is shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                               Catalyst/                                                                     Substrate   Percent                                    Example                Molar Ratio Yield                                      NO.     Catalyst       (mole %)    (%)                                        ______________________________________                                        6       RuBr.sub.3     5           88                                         7       Ru(OAc).sub.3  5           83                                         8       Ru.sub.3 (CO).sub.12                                                                         5           62                                         9       Ru(NO)Cl.sub.3.H.sub.2 O                                                                     5           51                                         10      1% Ru-on-graphite                                                                            5           78                                         11      5% Ru-on-carbon                                                                              5           56                                         12      5% Ru-on-alumina                                                                             5           31                                         13      OsCl.sub.3     2           84                                         14      CoCl.sub.2     10          23                                         ______________________________________                                    

The titled compound was also prepared in the same manner as above byusing each of Ru(TPP)(CO)-THF, RuCl₂ (PPh₃)₃, and Ru(acac) (wherein acacrepresents acetylacetonato) as a catalyst.

EXAMPLES 15 TO 20 Synthesis of (1'R, 3R,4R)-4-Acetoxy-3-[1'-t-butyldimethylsilyloxy)ethyl]azetidin-2-one

The titled compound was prepared in the same manner as in Example 1,except for using 458 mg (2 mmole) of (1'R,3S)-3-(1'-t-butyldimethylsilyloxy)ethyl]azetidin-2-one as a substrate,replacing acetaldehyde with each of the aldehyde compounds shown inTable 3 below, using 41 mg (0.5 mmole) of anhydrous sodium acetate, 26mg (0.1 mmole, 5 mole % based on the substrate) of ruthenium chloridetrihydrate, 1 ml of acetic acid, 20 ml of ethyl acetate, 40 ml of a 10%sodium sulfite aqueous solution, and 50 ml of a saturated sodiumchloride aqueous solution, and conducting the extraction with two 100 mlportions of n-hexane. The percent yield in each reaction is shown inTable 3.

                  TABLE 3                                                         ______________________________________                                                                 Amount of  Percent                                   Example                  Aldehyde   Yield                                     No.     Aldehyde         (mmole)    (%)                                       ______________________________________                                        15      propionaldehyde  5          88                                        16      hexanal          5          90                                        17      decanal          5          57                                        18      isobutylaldehyde 5          86                                        19      cyclohexanecarbaldehyde                                                                        5          78                                        20      crotonaldehyde   20         27                                        ______________________________________                                    

EXAMPLE 21 Synthesis of (1'R, 3R,4R)-4-Acetoxy-3-[(1'-t-butyldimethylsilyoxy)ethyl]azetidin-2-one

A mixture of 458 mg (2 mmole) of (1'R,3S)-3-[(1'-t-butyldimethylsilyloxy)ethyl]azetidin-2-one, 41 mg (0.5mmole) of anhydrous sodium acetate, 26 mg (0.1 mmole ) of rutheniumchloride trihydrate, 1 ml of acetic acid, and 20 ml of ethyl acetate washeated to 40° C., and 6.0 g (57 mmole) of benzaldehyde was added to thesolution, followed by stirring while blowing oxygen for 5 hours.

The reaction mixture was poured into 40 ml of a 10% sodium sulfiteaqueous solution and extracted twice with 100 ml portions of n-hexane.The extract was washed with 50 ml of a saturated sodium chloride aqueoussolution and dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under reduced pressure, and the residue waspurified by silica gel column chromatography using a 3:1 (by volume)mixed solvent of n-hexane and ethyl acetate to obtain 178 mg (0.69mmole, percent yield: 30%) of the titled compound.

EXAMPLE 22 Synthesis of (1'R, 3R,4R)-3-[(1'-t-butyldimethylsilyloxy)ethyl]-4-ethylcarbonyloxyazetidin-2-one

The titled compound was synthesized in the same manner as in Example 1,except for replacing azetidin-2-one with 458 mg (2 mmole) of (1'R,3S)-3-[(1'-t-butyldimethylsilyloxy)ethyl]azetidin-2-one, replacingacetaldehyde with 0.36 ml (5 mmole) of propionaldehyde, replacing aceticacid with 0.75 ml (10 mmole) of propionic acid, using 41 mg (0.5 mmole)of anhydrous sodium acetate, 26 mg (0.1 mmole ) of ruthenium chloridetrihydrate, 20 ml of ethyl acetate, 40 ml of a 10% sodium sulfiteaqueous solution, and 50 ml of a saturated sodium chloride aqueoussolution, and conducting the extraction with two 100 ml portions ofn-hexane. The yield was 500 mg (1.95 mmole, 85% ).

Melting point: 84.5° C.

¹ H-NMR (270 MHz, CDCl₃) δ ppm: 0.06 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H,t-Bu), 1.16 (t, J=7.6, 3H), 1.26 (d, J=6.4, 3H), 2.37 (q, J=7.6, 2H),3.18 (dd, J=3.7, 1.2, 1H), 4.22 (dq, J=6.4, 3.7, 1H), 5.84 (d, J=1.2,1H), 6.44 (bs, 1H, NH)

EXAMPLES 23 TO 31

Each of the 4-acyloxyazetidinone compounds shown in Table 4 below wassynthesized in the same manner as in Example 1, except for using 458 mg(2 mmole) of (l'R,3S)-3-[(1'-t-butyldimethylsilyloxy)ethyl]azetidin-2-one as a substrate,10 mmole of each of the carboxylic acids shown in Table 4, 41 mg (0.5mmole ) of anhydrous sodium acetate, 26 mg (0.1 mmole ) of rutheniumchloride trihydrate, 20 ml of ethyl acetate, 0.28 ml (5 mmole) ofacetaldehyde, 40 ml of a 10% sodium sulfite aqueous solution, and 50 mlof a saturated sodium chloride aqueous solution, and conducting theextraction with two 100 ml portions of n-hexane. The yield andanalytical results of the product are shown in Table 4. In the formulaein Table 4, Ph represents a phenyl group; t-Bu represents a t-butylgroup; and Me represents a methyl group.

                                      TABLE 4                                     __________________________________________________________________________                                               Melt-                                                                    Percent                                                                            ing .sup.1 H-NMR Spectrum          Example                                                                            Carboxylic                                                                             Produced 4-Acyloxy-     Yield                                                                              Point                                                                             (270 MHz, CDCl.sub.3)          No.  Acid     azetidinone Compound    (%)  (°C.)                                                                      (δ ppm)                  __________________________________________________________________________    23   ClCH.sub.2 CO.sub.2 H                                                                   ##STR16##              92   109 0.07(s, 3H), 0.08(s, 3H),                                                     0.87(s, 9H), 1.27(d, J=6.3                                                    H), 3.24(dd, J=3.3, 1.2,                                                      1H), 4.10(s, 2H), 4.24(dq,                                                    J=3.3, 6.3, 1H), 5.94(d,                                                      J=1.2, 1H), 6.44(b, 1H,                                                       NH)                                          (1'R,3R,4R)-3-(1'-t-butyl-                                                    dimethylsilyloxy)ethyl-4-                                                     chloroacetoxyazetidin-2-one                                     24   Cl.sub.2 CHCO.sub.2 H                                                                   ##STR17##              70   118 0.07(s, 3H), 0.08(s, 3H),                                                     .87(s, 9H), 1.28(d, J=6.4,                                                    H), 3.32(dd, J=3.3, 1.2,                                                      1H), 4.25(dq, J=3.3, 6.3,                                                     1H), 5.96 (s, 1H), 6.00(d,                                                    J=1.2, 1H) 6.50(b, 1H,                                                        NH)                                          (1'R,3R,4R)-3-)1'-t-butyl-                                                    dimethylsilyloxy)ethyl-4-                                                     dichloroacetoxyazetidin-2-one                                   25   BrCH.sub.2 CO.sub.2 H                                                                   ##STR18##              78   107 0.06(s, 3H), 0.08(s, 3H),                                                     0.87(s, 9H), 1.26(d, J=6.3                                                    H), 3.24(dd, J=3.4, 1.2                                                       1H), 3.86(s, 2H), 4.23(dq,                                                    J=3.4, 6.3, 1H), 5.92(d,                                                      J=1.2, 1H), 6.49(b, 1H,                                                       NH)                                          (1'R,3R,4R)-3-(1'-t-butyl                                                     dimethylsilyloxy)ethyl-4-                                                     bromoacetoxyazetidin-2-one                                      26   Br.sub.2 CHCO.sub.2 H                                                                   ##STR19##              65   105.5                                                                             0.07(s, 3H), 0.09(s, 3H),                                                     0.87(s, 9H), 1.28(d,                                                          J=6.4, 3H), 3.28(dd,                                                          J=3.4, 1.2, 1H), 4.25(dq,                                                     J= 3.4, 6.4, 1H), 5.82 (s,                                                    1H), 5.99(d, J=1.2, 1H),                                                      6.49(b, 1H, NH)                              (1'R,3R,4R)-3-(1'-t-butyl-                                                    dimethylsilyloxy)ethyl-4-                                                     dibromoacetoxyazetidin-2-one                                    27   CH.sub.3 OCH.sub.2 CO.sub.2 H                                                           ##STR20##              74   80  0.07(s, 3H), 0.09(s, 3H),                                                     0.87(s, 9H), 1.26(d,                                                          J=6.4, 3H), 3.22(dd,                                                          J=3.4, 1.2, 1H), 4.07(s,                                                      2H), 4.22(dq, J=6.4, 3.4,                                                     1H), 5.94(d, J=1.2, 1H),                                                      6.47(b, 1H, NH)                              (1'R,3R,4R)-3-(1'-t-butyl-                                                    dimethylsilyloxy(ethyl-4-                                                     methoxyacetoxyazetidin-2-one                                    28   PhCH.sub.2 CO.sub.2 H                                                                   ##STR21##              83   61  0.04(s, 3H), 0.06(s, 3H),                                                     0.85(s, 9H), 1.23(d,                                                          J=6.4, 3H), 3.18(dd,                                                          J=3.6, 1.2, 1H), 3.66(s,                                                      2H), 4.20(dq, J=3.6, 6.4,                                                     1H), 5.86(d, J=1.2, 1H),                                                      6.48(b, 1H, NH),                                                              7.24-7.36(m, 5H,                                                              aromatic)                                    (1'R,3R,4R)-3-(1'-t-butyl-                                                    dimethylsilyloxy)ethyl-4-                                                     phenylacetoxyazetidin-2-one                                     29   2,4-dinitro- benzoic acid                                                               ##STR22##              54   148 0.09(s, 3H), 0.10(s, 3H),                                                     0.90 (s, 9H), 1.30(d,                                                         J=6.3, 3H), 3.29 (dd,                                                         J=2.9, 1.2, 1H), 4.28(dq                                                      J=2.9, 6.3, 1H), 6.20(d,                                                      J=1.2, 1H), 6.53(b, 1H,                                                       NH), 7.94(d, J=8.6, 1H),                                                      8.57(dd, J=8.6, 2.2, 1H),                                                     8.84(d, J=2.2, 1H)                           (1'R,3R,4R)-3-(1'-t-butyl-                                                    dimethylsilyloxy)ethyl-4-                                                     (2,4-dinitrobenzoyloxy)-                                                      azetidin-2-one                                                  30   cyano- acetic acid                                                                      ##STR23##              81   117 0.06(s, 3H), 0.08(s, 3H),                                                     0.87 (s, 9H), 1.27(d,                                                         J=6.4, 3H), 3.27 (dd,                                                         J=3.2, 1.2, 1H), 3.52(s,                                                      2H), 4.24(dq, J=3.2, 6.4,                                                     1H), 5.96(d, J=1.2, 1H),                                                      6.53(b, 1H, NH)                              (1'R,3R,4R)-3-(1'-t-butyl-                                                    dimethylsilyloxy)ethyl-4-                                                     cyanoacetoxyazetidin-2-one                                       31* n-hexanoic acid                                                                         ##STR24##              61   60  0.06(s, 3H), 0.08(s, 3H),                                                     0.88 (s, 9H), 0.90(t,                                                         J=6.8, 3H), 1.25(d, J=6.1,                                                    3H), 1.32(m, 4H), 1.64(tt,                                                    J=7.6, 7.3, 2H), 2.34(t,                                                      J=7.3, 2H), 3.17(dd,                                                          J=3.7, 1.2, 1H), 4.22(dq,                                                     J=3.7, 6.1, 1H), 5.84(d,                                                      J=1.2, 1H), 6.49(b, 1H,                                                       NH)                                          (1'R,3R,4R)-3-(1'-t-butyl-                                                    dimethylsilyloxy)ethyl-4-                                                     pentylcarbonyloxyazetidin-                                                    2-one                                                           __________________________________________________________________________     Note:                                                                         *Acetaldehyde was replaced with 0.6 ml (5 mmole) of nhexanal.            

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A process for preparing a 4-acyloxyazetidinone ora derivative thereof represented by formula (IV): ##STR25## wherein R¹represents a hydrogen atom, a lower alkyl group, a hydroxyethyl group,or a protected hydroxyethyl group; R³ represents an alkyl group havingfrom 1 to 10 carbon atoms which may be substituted with a halogen atom,a cyano group, a lower alkoxy group or a phenyl group, or a substitutedor unsubstituted phenyl group, wherein said substituted phenyl group issubstituted with p-chlorophenyl, p-ethoxyphenyl, or 2, 4-dinitrophenyl,provided that the α-positioned carbon atom of said alkyl group shouldnot have more than two halogen atoms; and R⁴ represents a halogen atom,a lower alkyl group or a lower alkoxycarbonyl group, which comprisesreacting azetidinone or a derivative thereof represented by formula(II): ##STR26## wherein R¹ is as defined above, and R² represents ahydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, or acarboxyl group,with a carboxylic acid represented by formula (III):

    R.sup.3 COOH                                               (III)

wherein R³ is as defined above, in the presence of (1) a rutheniumcompound selected from Ru(NO)Cl₃ ·H₂ O, Ru(NO)Br₃ ·H₂ O, K(RuO₄) orBa(RuO₃ (OH)₂), (2) an aldehyde having 2 or more carbon atoms, providedthat the carbon atom at the α-position thereof should not have two ormore halogen atoms, and (3) oxygen.
 2. A process as claimed in claim 1,wherein said aldehyde having 2 or more carbon atoms is selected from thegroup consisting of alkylaldehyde and acetaldehyde substituted with ahalogen atom, a phenyl group, a lower alkoxy-substituted phenyl group ora halogen-substituted phenyl group.
 3. A process as claimed in claim 1,wherein said aldehyde having 2 or more carbon atoms is selected from thegroup consisting of acetaldehyde, propionaldehyde, hexanal, decanal,isobutyraldehyde, cyclohexanecarbaldehyde, crotonaldehyde andbenzaldehyde.
 4. A process as claimed in claim 1, wherein said rutheniumcompound is Ru(NO)Cl₃ ·H₂ O.
 5. A process as claimed in claim 1, whereinsaid ruthenium compound is K(RuO₄).
 6. A process as claimed in claim 1,wherein the reaction is carried out in the presence of a carboxylic acidsalt.